Table 1.

E1 and E2 Enzymes Inhibitors

E1 Enzyme Inhibitors	Effects on cancer cells	Ref.
Panepophenanthrin	Inhibit the binding of ubiquitin to E1, but has no inhibitory effect on cell growth. [further studies are needed]	[10]
Himeic acid A	Inhibitory effect on E1 catalytic activity	[12]
Largazole	Induce G1 phase arrest, which is associated with increased expression of p21 and the recruitment of HDAC1 to E2F1 that results in the proteasomal degradation of E2F1	[13]
Hyrtioreticulins A and B	Potent inhibitory ability against the formation of an E1-ubiquitin intermediate	[14]
PYR-41	Irreversible inhibitor of E1, inhibit the activation of NF-ҡB, and preventing the proteasome-mediated degradation of IκBα as well as p53	[17]
JS-K	Reduction of total ubiquitylated proteins, increased levels of p53 expression	[19]
NSC624206	Preventing the ubiquitin-thioester formation step, but has no effect on ubiquitin adenylation in the E1 activation reaction	[18]
MLN4924	Attenuates the function of the various CRLs	[20]
5′-O-sulfamoyl-N(6)-[(1S)-2,3-dihydro-1H-inden-1-yl]-adenosine (Compound I)	Nonselective UAE-inhibitory activity, forming a covalent adduct Ub-I, thereby inhibiting UAE-dependent ATP-PPi exchange activity and E1-E2 transthiolation	[27]
MLN7243	UBA1-selective inhibitor	[28–30]
ABPA3	Dual inhibitor of the Ub and NEDD8 E1s	[31]
Deoxyvasicinone-based compounds:    -  Dipeptide-conjugated deoxyvasicinone derivative    -  Valine-linked deoxyvasicinone derivative    -  N-isopropyl-linked deoxyvasicinone derivative	NAE-inhibitory effects through disrupting the ATP-binding domain [Biological effects and human cancers remain unknown].	[32,33]
Piperacillin 1	A reversible ATP-competitive inhibitor of NAE; increasing levels of the CRL substrate p27kip1	[34]
M22 (1-benzyl-N-(2,4-dichlorophenethyl) piperidin-4-amine)	Inhibitory activities of NAE against human cancers [further studies are needed]	[35]
LP0040 (2H-chromen-2-one derivative with phenyl substituents )	Inhibitory activities of NAE against human cancers [further studies are needed]	[36]
E2 Enzyme Inhibitors
Peptoid compound (Leucettamol A)	Disrupting the formation of the Ubc13–Uev1A complex, and inactivating of NF-kB and sensitization of tumor cells to chemotherapeutic agents	[40,41]
Dimeric sterols (Manadosterols A and B)	Antagonizing the Ubc13–Uev1A interaction, and more potent than Leucettamol A	[42]
NSC697923	Induce cancer cell apoptosis, cell death, initiating cell death by activating JNK pathway	[43]
CC0651	Disrupting the activity of human E2 enzyme Cdc34	[45]
Triazines compounds	Rad6B-inhibitory activities on levels of its conjugation to both ubiquitin and the substrate H2A	[47]